We have previously demonstrated that myocardial ischemia can be induced in patients with hypertrophic cardiomyopathy by rapid atrial pacing, precipitating symptoms of chest pain and shortness of breath identical to symptoms described by history. In order to elucidate mechanisms of myocardial ischemia in patients with hypertrophic cardiomyopathy and to assess whether the presence of obstruction in left ventricular outflow mattered in the pathogenesis of ischemia, 50 patients with hypertrophic cardiomyopathy and normal epicardial coronary arteries underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (mean left ventricular outflow gradient 77 plus or minus 33 mmHg) had significantly lower coronary resistance and higher basal coronary flow than the 27 patients without basal obstruction. During the stress of pacing, myocardial oxygen consumption and blood flow were significantly higher in patients with obstruction compared to patients without outflow obstruction. At a heart rate of 130, when most patients with obstruction, with myocardial ischemia occurring at a significantly lower flow and higher coronary resistance and lower myocardial oxygen consumption in the patients without obstruction. This study suggests that the elevated left ventricular systolic pressures associated with left ventricular outflow obstruction significantly increases myocardial oxygen demands and results in rapid exhaustion of coronary flow reserve during stress. In patients without basal obstruction, exhaustion of flow reserve at a lower peak flow suggests significant impairment in coronary flow delivery.